Format

Send to

Choose Destination
Free Radic Biol Med. 2014 May;70:106-16. doi: 10.1016/j.freeradbiomed.2014.01.018. Epub 2014 Feb 22.

GPx8 peroxidase prevents leakage of H2O2 from the endoplasmic reticulum.

Author information

1
Division of Molecular and Systems Toxicology, Department of Pharmaceutical Sciences, University of Basel, 4056 Basel, Switzerland.
2
Department of Biology, University of Copenhagen, 2200 Copenhagen N, Denmark.
3
Faculty of Life Sciences, Kyoto Sangyo University, Kyoto 803-8555, Japan.
4
Division of Molecular and Systems Toxicology, Department of Pharmaceutical Sciences, University of Basel, 4056 Basel, Switzerland. Electronic address: Christian.Appenzeller@unibas.ch.

Abstract

Unbalanced endoplasmic reticulum (ER) homeostasis (ER stress) leads to increased generation of reactive oxygen species (ROS). Disulfide-bond formation in the ER by Ero1 family oxidases produces hydrogen peroxide (H2O2) and thereby constitutes one potential source of ER-stress-induced ROS. However, we demonstrate that Ero1α-derived H2O2 is rapidly cleared by glutathione peroxidase (GPx) 8. In 293 cells, GPx8 and reduced/activated forms of Ero1α co-reside in the rough ER subdomain. Loss of GPx8 causes ER stress, leakage of Ero1α-derived H2O2 to the cytosol, and cell death. In contrast, peroxiredoxin (Prx) IV, another H2O2-detoxifying rough ER enzyme, does not protect from Ero1α-mediated toxicity, as is currently proposed. Only when Ero1α-catalyzed H2O2 production is artificially maximized can PrxIV participate in its reduction. We conclude that the peroxidase activity of the described Ero1α-GPx8 complex prevents diffusion of Ero1α-derived H2O2 within and out of the rough ER. Along with the induction of GPX8 in ER-stressed cells, these findings question a ubiquitous role of Ero1α as a producer of cytoplasmic ROS under ER stress.

KEYWORDS:

Apoptosis; Endoplasmic reticulum stress; Free radicals; Hydrogen peroxide; Peroxidases; Redox homeostasis

[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center